In 1997, it was estimated that 15.7 million people in the United States had diabetes, of which about 10.3 million were diagnosed and 5.4 million were undiagnosed. Due to the American lifestyle of poor diet and being overweight, the incidence of diabetes is becoming of epidemic proportions. Type II diabetes accounts for 90 to 95% of all cases of diabetes in the Untied States, making it and its attendant clinical and economic consequences a major public health problem. While the prevalence of diabetes in the Unites States is about 5% of the population, care for diabetes accounts for about 15% of health care expenses.
The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels. Most cases of type I diabetes are detected soon after symptoms develop, which is not the case for type II diabetes. Individuals with undiagnosed type II diabetes are at significantly higher risk for coronary heart disease, stroke, and peripheral vascular disease than the non-diabetic population. They also have a greater likelihood of having dyslipidemia, hypertension, and obesity. Early detection can reduce the burden of type II diabetes and its complications as well as lessen the economic consequences.
Testing for diabetes can generally be divided into two categories, diagnostic testing and screening. “Indicating diabetes” is used herein to refer to either, or both, of these. When an individual exhibits symptoms or signs of the disease, diagnostic tests are performed and such tests confirm whether the disease is present. The purpose of screening is to identify a generally asymptomatic individual who is at high risk to develop the disease or is in the very early stages of the disease when symptoms are difficult to identify. Two screening devices have been developed for diabetes, both of which are questionnaires based on risk factors for diabetes.
In 1993, the ADA disseminated a questionnaire titled “Take the Test. Know the Score”. This questionnaire assessed both possible symptoms and historical risk factors. Points were given for certain responses; a score of less than or equal to 5 points was considered low risk for diabetes, and a score of greater than 5 points was considered high risk. Subsequent testing among both United States and United Kingdom populations found that the test performed rather poorly. Two years later, another questionnaire was developed in the United States with data from the Second National Health and Nutritional Examination Survey. A test of the questionnaire in the population from which it was developed found a sensitivity of 79% (i.e., 79% of the diabetics were identified as diabetics), a specificity of 65% (i.e., 35% of the non-diabetics were identified as diabetics), and a PPV (positive predictive value) of 10% (i.e., a positive indication from the screen means the subject has a 10% chance of actually having diabetes).
Another questionnaire, developed in the Netherlands' Hoorn Study population, incorporated possible symptoms, demographic and clinical characteristics, and exercise preferences. When it was subsequently evaluated in a separate subgroup of the Hoorn Study population, this questionnaire was found to have a sensitivity of 56%, a specificity of 72%, and a performance slightly better than the ADA questionnaire for this population.
In summary, diabetes screening questionnaires, even with attempts to identify symptoms, perform rather poorly as stand-alone screening tests. Further, they are evidence of the need for an accurate screening test to identify those at high risk of developing diabetes or those in the early stages of diabetes prior to development of symptoms present at a later disease state.
In contrast to the screening questionnaires, two types of tests are currently acceptable diagnostic devices for diabetes. The fasting plasma glucose (FPG) test requires no consumption of food or beverage other than water for eight hours prior to testing. An intravenous sample of blood is drawn and tested. If the FPG test yields a glucose level in excess of 126 mg/dl, the test must be repeated at a later date. If both FPG glucose values are in excess of 126 mg/dl, the patient is diagnosed as having diabetes. The oral glucose tolerance test (OGTT) consists of a 75 g oral glucose challenge. A two-hour post load sample of blood with a value of 200 mg/dl or higher is also an indication for re-testing. While the OGTT is the more accurate of the two, the FPG is less demanding of the subject's time and is usually recommended for its convenience rather than for its accuracy.
The ADA recommends using invasive tests based on blood which are used for the diagnosis of diabetes to be also used as screening devices. The criteria is if a fasting plasma glucose (FPG) test yields a value of 126 mg/dl or higher; or if a casual plasma glucose test yields a value of 200 mg/dl or higher; or if a 75-g OGTT yields a value of 200 mg/dl or higher 2 hours later, the patient is a candidate for diagnosis of diabetes. If on a second day, one of the criteria is met a second time, then a diagnosis of diabetes is justified. It is, however, believed that these tests do not provide screening capability, as they are unlikely to identify those at risk of developing diabetes or those in the early stages of the disease.
Another set of diabetes-related tests are known which are not utilized for screening or diagnosis, but rather as a measure of the patient's long-term compliance with the therapeutic program and the patient's control of the disease. These tests are based on glycosylated proteins. Glucose will attach in a covalent bond to proteins at a rate proportional to the glucose level. This process is irreversible so the protein will remain glycosylated for the rest of its life. The accumulation of glycosylated proteins is dependent on the average life of the protein. Fructosamine is the product of glycosylated serum proteins which have a normal turn-over rate of two to three weeks. Hence, fructosamine is a marker of glucose control over the previous month. While there are some commonly available test instruments for fructosamine, they are not commonly accepted by diabetologists due to the short time window. Glycosylated hemoglobin (HbA1c) is the result of glycosylation of red blood cells which have a normal turn-over of eight to ten weeks. Hence, HbA1c is a marker for glucose control for the previous two to three months. One other glycosylation process that has been noted is glycosylated collagen (furosine). Glycosylated collagen has a very long life and a slow turn-over. As much as a thirteen-fold increase in glycosylated collagen has been found in some diagnosed diabetic patients.
The concept of using multivariate methods to classify elements into their parent populations was first put forward by Fisher in 1936. With the emergence of the computer in the 1960s, a number of authors proposed using different techniques for the computer diagnosis of disease. The techniques proposed included linear discriminant analysis (LDA), quadratic discriminant analysis (QDA) and logistic regression (LR). The diagnosis of diabetes using multivariate techniques was proposed by Gleser in 1972 where it was recommended to combine the OGTT results with other environmental factors such as age, sex, weight, etc.
Geladi et al. conducted a study that looked at using multivariate near-infrared (NIR) spectroscopic measurements with diabetics and non-diabetics. The article discussed the consequences of the changes in the microarteries and the resultant decreased blood flow resulting in tissue edema. The article discusses the use of Multi-frequency Bioelectric Impedance Analysis as well as near-infrared spectroscopy to detect the skin damage. The authors note a difference in the spectra between diabetics and nondiabetics, relating the differences to damage of the microarteries.